Various therapeutically active substances are not able to be administered in a pure form. It is frequently necessary to blend the active substances with other components so that a preparation is produced which is ready for use. Dependent on the chemical properties of the pharmacologically active substance it is necessary to take various considerations into account before a pharmaceutical preparation may be used for humans or animals.
When therapeutically active substances are to be administered parenterally it is usually necessary for the active substance in the form of a solid to be dissolved as a solution. Conventionally water is found to be a suitable solvent. If however the active substances are no more than sparingly soluble, it is not possible to produce any concentrated aqueous solutions for parenteral application, even though a comparatively high concentration of active substance would be desirable in order to avoid injection of an excessive volume which would not be well tolerated. In the art there has been a proposal to use cosolvents in order to bring sparingly soluble substances into solution. However, when more especially used in a highly concentrated form without or with only a small amount of added water, such cosolvents involve the disadvantage--more significantly in the case of intramuscular injections--of being poorly tolerated. There are then likely to be an induration (hardening of tissue), hemorrhage (bleeding) and/or necrosis (local death of tissue) at the injection site.
The use of tetrahydrofurfuryl alcohol polyethylene glycol as a solvent for parenteral preparations is mentioned in the Journal of Pharmaceutical Sciences, 52, page 917 ff (1963) where it is stated that undiluted application leads to irritation. This publication also describes the use of polyethylene glycols. It is stated here that the intramuscular injection of polyethylene glycol with a mean molecular weight of 300 may cause ischemic (bloodless) necroses in the muscular fascicle. These results were obtained from experiments on animals.
There is further literature confirming the view that polyethylene glycol should not be used in overly high concentrations. In a catalog of pharmaceutical adjuvants, which has been compiled by a working group organized by the companies Ciba-Geigy, Hoffmann-LaRoche and Sandoz, it is pointed out that the maximum concentration of polyethylene glycol with a mean molecular weight of 300 in solutions for parenteral administration amounts to about 30%. At a concentration in excess of 40% a hemolytic effect of polyethylene glycol with a mean molecular weight of 300 (PEG 300) was found to occur.
This finding has been also confirmed in Tieraerztliche Rundschau, 42, page 912 ff (1987) by O. Kern. It was found that the intramuscular injection of undiluted PEG 300 caused ischemic necrosis in rats. Furthermore it was found that an intramuscular injection of a 40% propylene glycol solution in water caused very pronounced tissue damage in various animals.
Thus it is to be seen from the prior art that different solvents may be utilized for parenteral preparations, if relatively low concentrations of these solvents are employed. The use of preparations which have a high percentage of such solvents may frequently lead to undesired side-effects.
The use of aqueous media for the pharmaceutical preparations is on the other hand not appropriate if the therapeutically active compound forms a sparingly soluble hydrate in the form of needles on contact with aqueous media. Thus in the case of therapeutically active compounds which are only sparingly soluble in water, more particularly triazole compounds, there is the danger of the hydrate crystallizing out in the form of needles. There is no need to explain that preparations intended for parenteral administration have to be in the form of a homogeneous solution without any possibility of crystallizing out from the solution.
Accordingly, one object of the present invention is to provide solvent mixtures which in the case of parenteral and more especially intramuscular administration are free of undesired side-effects while at the same time being capable of dissolving those therapeutically active substances, in a sufficient concentration and in stable manner, which are at the most only sparingly soluble in water.